The growing list of monogenic forms of neurodevelopmental disease includes mutations in at least 50 genes each encoding a different chromatin regulator. Remarkably, among these are five members of the lysine methyltransferase (KMT) and demethylase (KDM) family of molecules specifically targeting the K4 residue of the nucleosome core histone H3. These disease-associated mutations affect 3 KMTs, MLL1, MLL2, MLL3 and 2 KDMs, KDM5A and KDM5C/JARID1C/SMCX. However, very little is known about the molecular mechanisms by which H3K4-specific KMTs and KDMs regulate brain chromatin structure and function. MLL1, and its homologue, MLL2, are expressed at high levels in a large majority of neurons, but their specific effects on neuronal histone methylation landscapes and genome organization are from a genome-scale perspective still unclear. Here, we will apply conditional mutagenesis to explore the role of MLL1 and MLL2 for neuronal health and function, in conjunction with assays for working and long-term memory, social cognition and other behavioral paradigms. Furthermore, we will study synaptic plasticity, including spike timing-dependent short- and long-term potentiation and depression (sLTP and sLTD) in prefrontal and striatal circuitry of mice subject to neuron-specific methyltransferase deletion. We will apply some of the most innovative approaches in neuroepigenetics, including cell-type specific epigenome and transcriptome mappings in conjunction with chromosome conformation capture assays. We introduce radically novel hypotheses to the field. We propose that in neurons, H3K4 methylation is a mark essential for chromosomal loopings and physical interactions between gene-proximal promoters and distal enhancers, that are separated on the linear genome by thousands of kilobases. The work proposed here is expected to illuminate new principles of epigenetic regulation in the nervous system, and could pave the way for novel therapeutic approaches aimed at common neurodevelopmental and cognitive disorders, including autism and schizophrenia.